U.S. patent application number 09/811346 was filed with the patent office on 2002-01-03 for combined interferon alfa and lipsosmal-encapsulated all-trans retinoic acid, including preparation and use.
This patent application is currently assigned to Aronex Pharmaceuticals, Inc.. Invention is credited to Nanus, David.
Application Number | 20020001615 09/811346 |
Document ID | / |
Family ID | 26889129 |
Filed Date | 2002-01-03 |
United States Patent
Application |
20020001615 |
Kind Code |
A1 |
Nanus, David |
January 3, 2002 |
Combined interferon alfa and lipsosmal-encapsulated all-trans
retinoic acid, including preparation and use
Abstract
Alfa interferon (.alpha.-IFN or alpha-interferon) and liposomal
all-trans retinoic acid is useful in cancer treatment with
particular reference to renal cancer. Optionally, a regimen of
.alpha.-interferon from about 3 to about 5 million units sc daily
and liposomal all-trans retinoic acid at from about 15 mg/m.sup.2
to about 90 mg/m.sup.2, or about 140 mg/m.sup.2, or about 300
mg/m.sup.2 or more. Dosage periodicity of about three times per
week for both drugs in about 8 week cycles is useful.
Inventors: |
Nanus, David; (New York,
NY) |
Correspondence
Address: |
Thomas M. Saunders
Lorusso & Loud
440 Commercial Street
Boston
MA
02109
US
|
Assignee: |
Aronex Pharmaceuticals,
Inc.
|
Family ID: |
26889129 |
Appl. No.: |
09/811346 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60193565 |
Mar 31, 2000 |
|
|
|
Current U.S.
Class: |
424/450 ;
424/85.7; 514/559 |
Current CPC
Class: |
B82Y 5/00 20130101; A61K
38/21 20130101; A61K 38/21 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
424/450 ;
424/85.7; 514/559 |
International
Class: |
A61K 009/127; A61K
038/21; A61K 031/203 |
Claims
1. A method of inhibiting the growth of cancer cells comprising
exposing cancerous cells to a therapeutically effective amount of a
composition which comprises at least one interferon and a retinoid,
wherein said retinoid is associated with lipid carrier
particles.
2. The method of claim 1 wherein the retinoid is retinoic acid.
3. The method of claim 2 wherein the retinoic acid is all-trans
retinoic acid.
4. The method of claim 3 wherein lipid carrier particles comprise
all-trans retinoic acid, lipid, and a triglyceride and the molar
ratio of retinoid to lipid is at least about 15:85, where the
triglyceride is at least about 15% by weight of the composition,
and where the composition is stable in an aqueous environment.
5. The method of claim 1 comprising administering said retinoid
composition in doses administered over a period of at least
one-half hour.
6. The method of claim 1 comprising administering said retinoid
composition at a frequency of about every other day or less
frequent.
8. The method of claim 1 wherein the cancer is a renal cancer.
9. A method of inhibiting the growth of cancer cells comprising
exposing cancerous cells to a therapeutically effective amount of a
composition which comprises at least one interferon and further
co-timely exposing of said cancerous cells to a therapeutically
effective amount of a retinoid, wherein said retinoid is associated
with lipid carrier particles.
10. A therapeutic treatment kit for the treatment of cancer
comprising interferon, retinoid and instructional materials for the
combined use of said retinoid and interferon.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to Provisional application
No. 60/193,565 filed Mar. 31, 2000.
FIELD OF THE INVENTION
[0002] Alfa interferon (.alpha.-IFN or alpha-interferon) and
liposomal all-trans retinoic acid is useful in cancer treatment
with particular reference to renal cancer. Optionally, a regimen of
.alpha.-interferon from about 3 to about 5 million units sc daily
and liposomal all-trans retinoic acid (e.g., ATRAGEN.RTM., Aronex
Pharmaceuticals, The Woodlands, Tex.) at a dose from about 15
mg/m.sup.2 to about 90 mg/m.sup.2, or about 140 mg/m.sup.2, or
about 300 mg/m.sup.2 or more. Dosage periodicity of about five
times per week for both drugs in about 8 week cycles is useful. In
some instances interferon is dosed more often including every other
day and daily.
BACKGROUND OF THE INVENTION
[0003] The incidence of renal cell carcinoma is estimated to be
approximately 30,000 new cases annually, with a death rate of
10,000 patients per year (1). At the time of diagnosis
approximately fifty percent of patients have disease localized to
the kidney, thirty percent of patients have distant metastases, and
the remaining twenty percent of patients have locally advanced
disease (2). Currently, surgical resection of all discernible
disease is the only potentially curative therapy. For patients with
stage I or II disease, the five year survival ranges from 45 to
85%, while for patients with stage III disease the five year
survival ranges from 15 to 35% (2). Occasionally, selected patients
with stage IV disease have prolonged disease free survival after
resection of solitary metastases.
[0004] For those patients with surgically unresectable disease,
therapeutic options include chemotherapy, hormonal therapy and
immunotherapy. Unfortunately, all of these therapies are relatively
unsuccessful. Hormonal therapy has little or no therapeutic effect
(3). Similarly, available chemotherapy has been generally
ineffective. More than 40 drugs have been investigated, but none
achieved a response proportion greater than 15-20% alone or in
combination (4). The potential therapeutic benefit of biologic
response modifiers like interferons (IFN) have been studied in RCC
(5). Queseda, et al, first reported the clinical efficacy of human
leukocyte IFN in metastatic RCC (6). Subsequently, numerous
clinical trials with various subtypes of IFN including purified
human lymphoblastoid interferon-alpha and purified recombinant
interferon-alpha 2a and 2b have been performed. In these trials,
the proportion of patients experiencing major responses is only
about 15% (and a range of 5-29%), with a median duration of
response ranging from three to 16 months (5; 7). In a review of 18
trials of renal carcinoma treated with interferon-alpha, Krown et
al found no significant difference in response based on type or
schedule of drug (7). There was, however, evidence that moderate
doses of interferon-alpha produced superior response rates when
compared to either low or high doses. Thus, the overwhelming
majority of patients with RCC are unresponsive to the antitumor
effects of IFN given as a single agent (8; 9).
[0005] Other clinical trials have investigated the efficacy of
other biological response modifiers alone or in combination with
IFN a in the treatment of patients with metastatic RCC (10; 11).
Interleukin-2 (IL-2), with or without lymphokine-activated killer
(LAK) cells, has been extensively studied. Although initial
clinical trials reported significant numbers of major clinical
responses with IL-2, this was associated with significant toxicity
and few patients have shown long term clinical benefit (12; 13).
The addition of interleukin-2 (IL-2) to IFN resulted in a higher
number of clinical responses in patients with advanced RCC in one
study (14), however, this was not observed in subsequent trials
(15; 16). Overall, the data suggest that, similar to IFN a, the
proportion of patients experiencing significant responses with IL-2
based therapy is approximately 15% (17). It is clear that the need
exists for more effective therapy for patients with advanced renal
cancer.
[0006] A phase II trial of Interferon alfa-2a and free
(non-liposomal) 13-cis-retinoic acid (CRA) was conducted at
Memorial Sloan-Kettering Cancer Center (MSKCC) in patients with
advanced renal cell carcinoma (RCC). IFN was given daily; starting
at 3 million units (MU) and the dose was escalated every seven days
from 3 to 6 to 9 MU. The CRA was given daily at a dose of 1
mg/kg/day. Thirteen (30%) of 43 evaluable patients achieved a major
response (three complete, ten partial) (34). In addition to lung
and nodal metastases, responding sites included bone metastases and
renal primary tumors.
[0007] Other trials have also reported using a combination of
13-cis retinoic acid and IFN (36; 37). In one study examining the
pharmacokinetics of free all-trans retinoic acid (ATRA) in patients
with renal cancer concomitantly treated with IFN, peak levels of
atra in the serum declined after three months on therapy (38).
SUMMARY OF THE INVENTION
[0008] This invention comprises a method of inhibiting the growth
of cancer cells, and particularly renal cancer cells, comprising
exposing cancerous cells to a therapeutically effective amount of a
composition which comprises at least one interferon and a retinoid,
wherein said retinoid is associated with lipid carrier particles.
Particular note is made of the method the retinoid is retinoic
acid, such as all-trans retinoic acid.
[0009] In some embodiments of the method the lipid carrier
particles comprise all-trans retinoic acid, lipid, and a
triglyceride and the molar ratio of retinoid to lipid is at least
about 15:85, where the triglyceride is at least about 15% by weight
of the composition, and where the composition is stable in an
aqueous environment. In specific embodiment the method of comprises
administering said retinoid composition in doses administered over
a period of at least one-half hour, and, optionally, administering
said retinoid composition at a frequency of about every other day
or less frequent.
[0010] In another embodiment this invention comprises a method of
inhibiting the growth of cancer cells comprising exposing cancerous
cells to a therapeutically effective amount of a composition which
comprises at least one interferon and further co-timely exposing of
said cancerous cells to a therapeutically effective amount of a
retinoid, wherein said retinoid is associated with lipid carrier
particles.
[0011] A composition of the present invention comprises a
therapeutic treatment kit for the treatment of cancer comprising
interferon, retinoid and instructional materials for the combined
use of said retinoid and interferon. In some instances
instructional materials include such information as dosage,
indication, and contraindication and storage parameters.
DETAILED DESCRIPTION OF THE INVENTION
[0012] A. "Exposing" as used in relation to cancerous cells shall
mean in vivo and further include extra corporeal as will as in
vitro applications. In vitro applications are particularly useful
in diagnostic and screening applications of the present
invention.
[0013] B. Cancer shall be broadly understood to mean an abnormal
uncontrolled growth of tissue that has potential to spread to
distant sites of the body. In particular, cancer shall include
renal cell carcinoma including chromophobe cell renal carcinoma and
further granular/eosinophilic variants of these tumors and renal
oncocytoma, renal leiomyosarcoma. Particular note is made of head,
neck, and breast cancer. Head, neck, and breast cancer are often
found to have reduced retinoid levels. In specific instances tumor
cells presenting with low retinoid levels exhibit enhanced
therapeutic response to the instant therapy.
[0014] C. "Therapeutically effective amount" is defined
independently for each drug. As to L-ATRA a therapeutically
effective amount shall mean about 15-300 mg/m.sup.2 and
particularly 90 mg/m.sup.2.
[0015] As to interferon alfa a therapeutically effective amount
shall mean from about 1 to about 25 million IU and particularly 3-5
million IU.
[0016] It is anticipated that interferons alfa, beta, gamma, and
omega are administered in similar doses. Doses are generally
adjusted to at or below the maximum tolerated dose (MTD). Signs
indicative of interferon toxicity are noted to be as to hematologic
toxicity, anemia, thrombocytopenia, leukopenia: as to
gastrointestinal toxicity, diarrhea, dyspepsia, dysphagia, N/V,
abdominal pain; as to liver toxicity increases in bilirubin, alk
phos and LFTs; as to kidney and bladder, microscopic hematuria,
pyuria, azotemia, proteinuria, acute renal failure, nephrotic
syndrome, glycosuria, albuminuria; as to pulmonary, orthopnea,
dyspnea, bronchospasm, coughing, pulmonary edema, ARDS; as to
cardiac toxicity syncope, MI, SVT, bradycardia, tachycardia,
dizziness, hyptoension, hypertension. Neurological toxicity are
confusion, tremors, numbness, paresthesia, inability to
concentrate, somnolence, hallucinations, encephalopathy, seizure,
coma, psychomotor retardation, memory dysfunction, dry mouth,
sweating, personality disorder, agitation, neuropathy, depression,
anxiety, aphasia, retinal infarction with vision loss, eye pain,
hemianopsis, taste change, headache, syncope, insomnia. Dermal
toxicity of skin rash, urticaria, epidermal necrosis, maculopapular
rash is noted. Metabolic toxicity manifests as hyperglycemia. In
addition coagulation is monitored for increase in PT/PTT. Also the
presence of phyarngitis, alopecia, fatigue, malaise, anorexia,
weight loss, fever, chills, myalgia, arthralgia, cyanosis are
potential toxic responses to interferon.
[0017] Liposomal ATRA at toxic doses displays hematologic
thrombocytopenia. In addition gastrointestinal toxicity of N/V and
mucositis. Liver toxicity increase alk phos and LDH. Neurologic
toxicity results in emotional changes, and headache. Dermal
toxicity is noted in dry skin, dermatitis. Also, metabolic changes
are found in an increase in triglycerides levels in the blood.
Toxicity is also determined by alopecia, anorexia, dry eyes,
cheilitis, epistaxis, joint pain, fatigue, pruritus, and
conjunctivitis.
[0018] The foregoing not withstanding, a supervising clinician will
understand that initial myelosupression is a favorable sign in the
treatment of leukemias.
[0019] Without being bound by any particular theory it is believed
that retinoid effects are mediated through retinoic acid nuclear
receptors (RARs) which are members of the steroid receptor
superfamily of ligand-dependent transcriptional factors (25). Two
distinct retinoid nuclear receptor systems exist, the RARs (RAR-a,
-b, -g ) and the RXRs (RXR-a, -b, -g ) (26). The RARs and RXRs can
heterodimerize following RA binding, and transcriptionally activate
or repress other genes which mediate the growth and differentiation
effects of RA (26; 27).
[0020] D. "Interferon" shall be broadly understood to mean any of
several glycoproteins that help the body fight off viral
infections. Particular note is made of interferons alfa (or alpha),
beta, and gamma. Interferon alpha is the main type of interferon
produced by the white blood cells
[0021] Particular reference is made to interferon alfa-2b,
recombinant, (Intron A, Schering), and interferon alfa 2a (Roferon,
Hofman LaRoche).
[0022] E. "Retinoid" shall be broadly understood to mean the
natural and synthetic derivatives of vitamin A. Isotretinoin (13
cis-retinoic acid) and tretinoin (all trans retinoic acid)
represent the two naturally occurring isomers of retinoic acid
(18).
[0023] F. Lipid Carrier particle shall be expansively understood to
mean all lipid-drug particulates. Reference also is made to U.S.
Pat. No. 5,811,119, "Formulation and Use of Carotenoids in
Treatment of Cancer" to Mehta et al. Reference is further made to
U.S. Pat. No. 4,610,868 to Fountain. Fountain is a patent which
describes amorphous lipid particles, with particular reference to
Fountain col. 7, lines 1-17. Lipid carrier particles is a term
known in the art defining structures in addition to liposomes.
[0024] Particular reference is made to liposomal ATRA. In one
embodiment. Liposomal ATRA or liposomal tretinoin (also known as
liposomal ATRA Tretinoin.sup.LF or ATRAGEN.RTM.) is provide by
Aronex Pharmaceuticals, Inc (The Woodlands, Tex.). Without being
bound by any particular theory, the liposomal delivery system
improves the activity of the tretinoin by altering its
pharmacological profile, such as changing the drug's
pharmacokinetics and issue distribution. Once injected into the
bloodstream, liposomes are quickly cleared by the
reticuloendothelial system (RES) cells which include the liver and
spleen and, most importantly, the hematopoietic tissues from which
the malignant cells are seeded. Minimal liposomal uptake occurs in
tissues with continuous, non-fenestrated capillaries such as muscle
and nervous tissue.
[0025] Another beneficial difference is that the lipid formulation
bypasses the clearance mechanism that evolves in the livers of
patients treated with the oral formulation. In addition, toxicities
associated with oral doses of tretinoin are reduced in some cases
because liposome encapsulation of tretinoin decreases direct
exposure of the tretinoin during circulation to levels below the
orally administered toxic dose. The latter allows greater total
exposure of the drug on initial dose accompanied by slower
clearance of the tretinoin. This is also understood to be an
avoidance of ATRA resistance.
[0026] G. "Co-timely" as to drug administration shall mean
administration of interferon while L-ATRA is present in a
therapeutically effective amount or the reverse. It is to be
understood that in some instances this will require sequential
administration. In some instances, multiple routes of
administration will be employed such as intravenous or subcutaneous
injection of an alfa interferon, while a L-ATRA is administered
i.v. prior to or subsequent to such interferon administration.
[0027] Treatment is usefully employs liposomal ATRA in the form of
ATRAGEN.RTM.. A vial of lyophilized ATRAGEN.RTM. is reconstituted
with 50 ml of 0.9% sodium chloride for injection, USP, to provide a
2 mg per ml of liposomal suspension requiring no further dilution
steps. The vial is then shaken vigorously for one minute. This
forms a dispersion of ATRAGEN.RTM. liposomes. Several minutes is
then for the foaming of reconstituted product to subside prior to
transfer of the suspension. Due to the foaming of the reconstituted
product, approximately 5-10 mL of the 50 mL of product may not be
transferable. At this point, the reconstituted drug is aseptically
transferred into an I.V. bag or bottle. Alternatively, properly
cover the I.V. bag or bottle to sufficiently reduce light exposure
during infusion (I.V. lines do not generally require coverage. As
to interferon-alfa 2b, Inton A, (Schering Oncology)., this is
available as a reconstituted solution for injection in 3, 5 and 10
million IU vials. Each vial contains 3 (or 5 or 10) million IU of
Interferon alfa-2b, recombinant, dissolved in 0.5 ml (3 and 5
million unit vials) or 1 ml (10 million unit vials). Each 1 ml
contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic,
1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg
polysorbate 80, and 1.5 mg m-cresol as preservative. Vials are
stored in refrigerator (4.degree. C.) prior to use and is stable
for up to 7 days at 35.degree. C. and at 30.degree. C. for up to 14
days.
[0028] In some instances, interferon is administered s.c. Blood
levels tend to peak at about 4 hours. For patient comfort,
interferon is usefully administered in the evening so that a
subject will be asleep during the more severe side-effects.
Co-timely administration particular is noted to present
ATRAGEN.RTM. concentrations to coincide with interferon peaks. In
one embodiment, interferon is administered Monday through Friday
and ATRAGEN.RTM. Monday, Wednesday and Friday.
EXAMPLE 1
[0029] A 63 year old human male presented with metastatic renal
cancer. Alfa interferon and ATRAGEN.RTM. were administered as
follows:
[0030] Interferon at 5.times.10.sup.6 units s.c. daily Monday
through Friday, and ATRAGEN.RTM. 15 mg/m.sup.2 i.v., Monday,
Wednesday and Friday. This treatment was provided in 8 week cycles
resulting in regression of the cancer.
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[0070] All references cited are incorporated herein by
reference.
[0071] The compositions of this invention possess valuable
pharmacological properties. They inhibit neoplasm cell
proliferation and or angiogenesis in cancer therapy in human and
veterinary medicine. Administration is contemplated to include
chronic, acute or intermittent regimens.
[0072] The compositions are particularly useful in treating renal
cancers and other solid tumors.
[0073] In addition, the compositions can be used in in vitro
methodologies, including diagnostics or screening procedures (e.g.,
in an assay sensitive cancer types). In some embodiments, tissues,
cells or material treated in vitro or extra corporeally will,
thereafter, be reintroduced into a subject (which need not be the
source of origin of the tissue, cells or material). Compounds of
the present invention can be employed in admixture with carriers,
excipients and other drugs, and radiation therapy.
[0074] The compositions of this invention are generally
administered to animals, including but not limited to mammals such
as livestock, household pets, humans, cattle, cats, dogs, poultry,
etc.
[0075] The pharmacologically active compositions of this invention
can be processed in accordance with conventional methods of Galenic
pharmacy to produce medicinal agents for administration to
patients, e.g., mammals including humans.
[0076] The compositions of this invention can be employed in
admixture with conventional excipients, i.e., pharmaceutically
acceptable organic or inorganic carrier substances suitable for
parenteral, enteral (e.g., oral or inhalation) or topical
application which do not deleteriously react with the active
compositions. Suitable pharmaceutically acceptable carriers include
but are not limited to water, salt solutions, etc. The
pharmaceutical preparations can be sterilized and if desired mixed
with auxiliary agents, e.g. They can also be combined where desired
with other active agents, including radiation or other
antineoplastic therapy.
[0077] In some embodiments of the present invention, dosage forms
include instructions for the use of such compositions.
[0078] For parenteral application, particularly suitable are
injectable, sterile solutions, preferably suspensions. Ampules are
convenient unit dosages.
[0079] Sustained or directed release compositions can be
formulated, e.g., liposomes or those wherein the active component
is protected with differentially degradable coatings, e.g., by
microencapsulation, multiple coatings, etc. It is also possible to
freeze-dry the new compositions and use the lyophilizates obtained,
for example, for the preparation of products for injection.
[0080] Generally, the two compositions of this invention are
dispensed in unit dosage form comprising liposomal ATRA of from 15
to 300 or more mg/m.sup.2 and particularly about 90 mg/m.sup.2
ATRA. Interferon is administered at from about 1,000,000 to about
25,000,000 IU, and particularly from about 3,000,00 to about
5,000,000 sc and from daily to about 5 out of 7 days to about 3 out
of 7 days per week.
[0081] It will be appreciated that the actual preferred amounts of
active compositions in a specific case will vary according to the
specific compositions being utilized, the particular compositions
formulated, the mode of application, and the particular situs and
organism being treated. Dosages for a given host can be determined
using conventional considerations, e.g., by customary comparison of
the differential activities of the subject compositions and of a
known agent, e.g., by means of an appropriate, conventional
pharmacological protocol.
* * * * *